This project assesses the role that free radicals might play in the neurotoxic effects associated with amphetamine analogs. Towards that end, we determined the effects of drug of abuse on the dopamine and serotonin systems in adult transgenic mice which overexpress the scavenging enzyme, superoxide dismutase. Oxygen-based radicals are toxic compounds that have been implicated in the causation of a number of neurotoxic and neuropathological events. It was suggested that the deleterious effects of drugs of abuse, including the by-products of their synthesis, might be related to the production of oxygen-based and of other reactive compounds. Several enzymes including catalase, glutathione peroxidase, and superoxide dismutase, protect the cells form oxidative stress. Administration of methamphetamine (METH) also causes significant depletion in a number of mammalian species. The effects of METH were also tested in the SOD-Tg mice. In Non-Tg mice, acute METH administration caused significant decreases in DA and dihydroxyphenyl acetic acid (DOPAC) in the striata and cortices. In contrast, there were no significant changes in striatal or cortical DA in the SOD-Tg mice. Chronic administration of METH caused depletion of DA and DOPAC in only the striata of Non-Tg mice. We also tested the lethal effects of MDA and MDMA in these mice and found that the transgenic mice were also protected. These results suggest that amphetamine-induced neurotoxic and lethal effects might involve overwhelming oxidative stress to the organisms.